Episodic memory decline is commonly reported in the course of normal aging but often raises concern about incipient Alzheimer's disease (AD). Understanding the neural basis for memory decline early in the AD pathophysiological process is critical to facilitate earlier diagnosis, track disease progression and to evaluate the efficacyof potential therapies. Functional neuroimaging has already shown significant differences between young adults, normal elderly and patients with AD dementia in episodic memory tasks, particularly associative memory. More recently, my sponsor's group has found evidence of early functional and behavioral alterations in clinically normal older individuals with Alzheimer's pathology (e.g. amyloid- deposition) that suggest these individuals may be in the preclinical stages of AD. The neural underpinnings of memory dysfunction in preclinical AD remain to be more fully elucidated, particularly the influence of amyloid- on hippocampal function. The overall objective of this project to develop a novel fMRI paradigm that combines associative and transitive memory of face-name and face-occupation pairs to probe hippocampal function, and that may serve to better disambiguate the process of normal aging from the early stages of preclinical AD. This combination will better characterize the neural basis of episodic memory. This experimental design leverages two key ideas: (1) associative memory for face-name pairs is sensitive to aging effects, while face-occupation deficits may be indicative of amyloid- related dysfunction; and (2) impairment of transitive memory will be a more specific marker of AD related pathology, and will be less affected by age. The first specific aim is to validate that the neuroimaging task characterizes the neural differences between associative and transitive memory in young adults. The second specific aim assesses whether there are normal aging-related changes in the neural basis of episodic memory for associative memory and/or transitive memory by comparing young adults to older adults without evidence of amyloid- deposition on PiB-PET amyloid imaging. The third specific aim is to assess whether there are amyloid-dependent changes in the neural basis of episodic memory for associative memory and/or transitive memory by comparing individuals with and without any amyloid- deposition. The proposed project should serve to further our understanding of the neural mechanisms underlying episodic memory in the process of normal aging and the alterations in memory function that may represent preclinical stages of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an irreversible neurodegenerative disease effecting over 5.4 million Americans that already costs more than $200 billion annually, which necessitates the development of advanced neuroimaging techniques to facilitate earlier detection of disease. Thus, the aim of this proposal is to develop a neuroimaging paradigm and associated analyses that will be sensitive to functional differences between normal aging and pathological aging, in particular preclinical AD.